编码缺氧诱导因子 2α (HIF-2α) 的 EPAS1 中的致病变异 (PV) 可能是约 3%-6% 嗜铬细胞瘤和副神经节瘤 (PPGL) 的潜在遗传原因。 EPAS1 相关的 PPGL 可能作为孤立的肿瘤出现，也可能作为 Pacak-Zhuang 综合征 (PZS) 的一部分出现，并伴有 PPGL、红细胞增多症和生长抑素瘤三联症中的两个或多个。 HIF-2α 在细胞缺氧途径的调节中发挥着关键作用。当获得功能获得性 PV 时，HIF-2α 会逃避 2 型脯氨酰羟化酶 (PHD2) 的稳态羟基化，从而加速 von Hippel-Lindau (VHL) 介导的蛋白酶体降解。在这种情况下，HIF-2α 是稳定的并且可以易位到细胞核，诱导与肿瘤发生相关的多个基因的表达。这导致了PPGL和PZS其他表现形式的发展。 EPAS1相关的PPGL通常发生在二十岁或三十岁，女性中更常见，并且通常是多发的，肾上腺和肾上腺外的，并且分泌去甲肾上腺素。此外，这些肿瘤具有增加的转移潜力，据报道，高达 30% 的病例出现转移性疾病。虽然红细胞增多症在 PZS 中相当常见，但生长抑素瘤却很少见。有人认为，EPAS1 中获得的 PV 特征会影响其与 PHD2 的结合，并与 PZS 中的某些表型相关。在相关散发性 PPGL 中发现的 EPAS1 中的 PV 也与缺氧状况有关，包括紫绀型先天性心脏病、血红蛋白病和高海拔。了解缺氧途径及其在 PPGL 发病机制中的作用可能为开发这些肿瘤的有效疗法开辟新途径。事实上，这些疗法之一是 Belzutifan，一种 HIF-2α 抑制剂，正在测试用于治疗转移性 PPGL。版权所有 © 2024 Elsevier Ltd。保留所有权利。

Pathogenic variants (PVs) in EPAS1, which encodes hypoxia-inducible factor-2α (HIF-2α), could be the underlying genetic cause of about 3%-6% of pheochromocytoma and paragangliomas (PPGLs). EPAS1-related PPGLs may occur as isolated tumors or as part of Pacak-Zhuang Syndrome (PZS) with two or more of a triad of PPGL, polycythemia, and somatostatinoma. HIF-2α plays a critical role in the regulation of the cellular hypoxia pathway. When a gain-of-function PV is acquired, HIF-2α evades steady-state hydroxylation by the prolyl hydroxylase type 2 (PHD2), which accelerates von Hippel-Lindau (VHL)-mediated proteasomal degradation. In this situation, HIF-2α is stabilized and can translocate to the nucleus, inducing the expression of several genes involved in tumorigenesis. This leads to the development of PPGL and other manifestations of PZS. EPAS1-related PPGLs usually occur in the second or third decade of life, more frequently in females, and are usually multiple, adrenal and extra-adrenal, and norepinephrine-secreting. In addition, these tumors carry an increased metastatic potential and have been reported with metastatic disease in up to 30% of cases. While polycythemia is fairly common in PZS, somatostatinomas are rare. It has been suggested that the character of the acquired PV in EPAS1, which affects its binding to PHD2, correlates with certain phenotypes in PZS. PVs in EPAS1 that have been found in related sporadic PPGLs have also been associated with hypoxic conditions including cyanotic congenital heart disease, hemoglobinopathies and high altitude. Understanding the hypoxia pathway and its role in the pathogenesis of PPGL may open a new avenue for developing effective therapies for these tumors. Indeed, one of these therapies is Belzutifan, a HIF-2α inhibitor that is being tested in the treatment of metastatic PPGLs.Copyright © 2024 Elsevier Ltd. All rights reserved.